Hippo Pathway: Regulating Organ Size & Cell Proliferation

Background and Mechanism:

Interestingly, a few years ago it has been published in Nature magazine a study reporting that glucose, the main energy source used for energy generation in cells, regulates the Hippo pathway (specifically its downstream effector YAP)(Ref.). This is very interesting and ground breaking because with this research it has been indicated for the first time an exciting link between the glucose metabolism (glycolisis or fermentation) and the Hippo pathway and its relevance in tissue maintenance and cancer prevention.

This is also valuable since it links stronger two different views on cancer, i.e. cancer as a genetic disease and cancer as a metabolic disease.

So far we often discussed glucose metabolism (glycolisis or fermentation) but what is the Hippo Pathway?

The Hippo Pathway represents an intrinsic evolutionarily regulator of organ size essential to control and stop cell growth when the organ reaches its final size. It is involved in cell contact inhibition and controls organ size by regulating cell proliferation, apoptosis, and stem cell self renewal. Inactivation or dysregulation of this pathway leads to organ overgrowth and contributes to cancer development. (Ref1, Ref2)

The central components of this pathway comprise

a regulatory serine‑threonine kinase module and ( The kinase module includes the mammalian orthologues of Drosophila mel– anogaster Hippo, mammalian STE20‑like protein kinase 1 (MST1; also known as STK4) and MST2 (also known as STK3), and in addition, the large tumour suppressor 1 (LATS1) and LATS2)

a transcriptional module ( The transcriptional module includes yes‑ associated protein (YAP) and transcrip‑ tional co‑activator with PDZ‑binding motif (TAZ; also known as WWTR1), which are two closely related paralogues that largely mediate the downstream effects of Hippo signalling)

When the inhibitory Hippo kinase module is ‘on’, LATS1 and LATS2 inactivate YAP and TAZ, and the output gene production is therefore turned off. On the other hand, when the kinase module is ‘off’, YAP and TAZ translocate into the nucleus and induce target gene expression. Accordingly, the components of the kinase module are tumour suppressors and those of the transcriptional module are oncogenes.

The Hippo pathway was initially thought to be quite straightforward; however, recent studies have revealed that YAP/TAZ is an integral part and a nexus of a network composed of multiple signaling pathways, and as a result there is a crosstalk between the Hippo pathway and other tumor-related pathways (see left figure). (Ref.)

Defects in Hippo signalling and hyperactivation of its downstream Yes-associated protein (YAP) and transcriptional co-activator with TAZ contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy.

Therefore, Yes-associated protein 1 (YAP1) is a protein that acts as a regulator by activating genes involved in cell proliferation and suppressing apoptotic genes. It is normally inhibited in the Hippo signaling pathway which allows the cellular control of organ size and tumor suppression, and is amplified in various human cancers. As a result, the YAP1 protein serves as a target for the development of new cancer drugs.

In summary, the Hippo pathway regulates organ size by inhibiting cell proliferation and promoting cell apoptosis upon its activation. It is is capable of sensing and responding to the physical organization of cells, coordinating these physical signals with chemical. This sensing is done via YAP and TAZ which in turn are regulated by soluble extra‑cellular factors, cell–cell adhesionns and mechanotransduction.

In this context, when it is active the Yes Associated Protein 1 (YAP1) affects the Hippo pathway such that promotes cell growth. In human cancer, the YAP1 gene was reported as amplified and over-expressed in several tumor types.

Note that recently it has also been identified that glucose-transporter 3 (GLUT3) is a YAP-regulated gene involved in glucose metabolism, indicating a potiantially oncogenic function of YAP in promoting glycolysis (i.e. the intensive demand of cancer cells for glucose) (Ref.)

The available data do suggest the possibility that YAP/TAZ activation may be a common end-point of pathways leading to malignant progression (Ref.) Therefore, targeting YAP may prove to be a fruitful approach for treatment of multiple human cancers with aberrant YAP activity. (Ref.)

According to the study indicated above (Ref.) inhibition of YAP may also lead to the reduction of the fermentation process in cancer cells.

Indeed, it has been suggested that YAP could be a promising therapeutic strategy for treatment of e.g.

Research suggests that drugs such as verteporfin, which interfere with cancer-promoting YAP function, might prove useful in Sox2-dependent tumors. (Ref.)

YAP inhibitor: Verteporfin

Verteporfin has been recently identified as YAP inhibitor:

Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP http://www.ncbi.nlm.nih.gov/pubmed/22677547 We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.

Verteporfin (trade name Visudyne), a benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye. However, only recetntly it has been identified as a YAP inhibitor.

YAP is also an authophagy activator inducing resistance to Chemo: As a photosensitizer, verteporfin generates large amounts of singlet oxygen upon light irradiation, which elicits a cell-death response. In the absence of light activation, verteporfin is nontoxic and inhibits (starvation- and drug-induced) autophagy. (Ref.)

10 minute in travenous infusion of Visudyne at a dose of 6 mg/m2 body surface area, diluted in in 5% glucose for injection to a final volume of 30 mL. This is the infusion solution (Ref.)

Toxicity

Most common side effects are blurred vision, headache, and local effects at the injection site. Also,photosensitivity; it is advised to avoid exposure to sunlight and unscreened lighting until 48 hours after the injection of verteporfin

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